DOCSLIB.ORG

Exome Sequencing Resolves Apparent Incidental Findings and Reveals Further Complexity of SH3TC2 Variant Alleles Causing Charcot

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Exome Sequencing Resolves Apparent Incidental Findings and Reveals Further Complexity of SH3TC2 Variant Alleles Causing Charcot Lupski et al. Genome Medicine 2013, 5:57 http://genomemedicine.com/content/5/6/57 RESEARCH Open Access Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy James R Lupski1,2*, Claudia Gonzaga-Jauregui1, Yaping Yang3, Matthew N Bainbridge2, Shalini Jhangiani2, Christian J Buhay2, Christie L Kovar2, Min Wang2, Alicia C Hawes2, Jeffrey G Reid2, Christine Eng3, Donna M Muzny2 and Richard A Gibbs1,2* Abstract Background: The debate regarding the relative merits of whole genome sequencing (WGS) versus exome sequencing (ES) centers around comparative cost, average depth of coverage for each interrogated base, and their relative efficiency in the identification of medically actionable variants from the myriad of variants identified by each approach. Nevertheless, few genomes have been subjected to both WGS and ES, using multiple next generation sequencing platforms. In addition, no personal genome has been so extensively analyzed using DNA derived from peripheral blood as opposed to DNA from transformed cell lines that may either accumulate mutations during propagation or clonally expand mosaic variants during cell transformation and propagation. Methods: We investigated a genome that was studied previously by SOLiD chemistry using both ES and WGS, and now perform six independent ES assays (Illumina GAII (x2), Illumina HiSeq (x2), Life Technologies’ Personal Genome Machine (PGM) and Proton), and one additional WGS (Illumina HiSeq). Results: We compared the variants identified by the different methods and provide insights into the differences among variants identified between ES runs in the same technology platform and among different sequencing technologies. We resolved the true genotypes of medically actionable variants identified in the proband through orthogonal experimental approaches. Furthermore, ES identified an additional SH3TC2 variant (p.M1?) that likely contributes to the phenotype in the proband. Conclusions: ES identified additional medically actionable variant calls and helped resolve ambiguous single nucleotide variants (SNV) documenting the power of increased depth of coverage of the captured targeted regions. Comparative analyses of WGS and ES reveal that pseudogenes and segmental duplications may explain some instances of apparent disease mutations in unaffected individuals. Keywords: Exome sequencing, Whole-genome sequencing, Incidental findings, SH3TC2, Personal genomes, Precision medicine * Correspondence: [email protected]; [email protected] 1Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA Full list of author information is available at the end of the article © 2013 Lupski et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lupski et al. Genome Medicine 2013, 5:57 Page 2 of 17 http://genomemedicine.com/content/5/6/57 Background databases and the lack of clinical indications for any of Exome sequencing (ES) is an approach to human genome these five conditions, led to the conclusion that these analysis and genetic variant detection that focuses on the alleles were most probably not pathogenic in the proband. coding exons of genes and closely linked functional ele- In the period since the initial CMT study, technologies ments. ES is less expensive than comparable approaches for both WGS and ES have advanced considerably. We based on whole genome sequencing (WGS), because developed a series of improved ES methods and reagents there is overall less raw DNA sequence data required. that reliably assay >95% of the coding regions of the Furthermore, coding regions contain the changes that are human genome [5,6]. The current ES assay design currently the most easily interpretable, and knowledge involves routine ‘oversampling’ of the targeted regions, gained from ES may therefore have more immediate med- and ensures that a minimum of 95% (average 97%) of ical utility and application. There is a generally held belief, these positions are tested with >20-fold NGS coverage. however, that WGS may be more informative than ES, The new methods also take advantage of longer indivi- even within the boundaries of exome regions, as the ran- dual DNA sequence reads generated on the Illumina dom distribution of individual sequence reads offers an HiSeq platform (2 × 100 bp) versus the previous SOLiD overall higher likelihood of effective testing of individual platform (2 × 50 bp) used for WGS. sites in the genome. Further, biases inherent to the cap- ture process may result in missing or poorly covered Methods bases in a subset of the exome regions [1]. Sample inclusion We previously applied WGS using massively parallel This study conforms to the Helsinki Declaration regarding next-generation sequencing (NGS) methods to a subject ethical principles for medical research involving human with molecularly undefined, autosomal recessive, Char- subjects. Subject BAB195 and additional family members cot-Marie-Tooth (CMT) neuropathy and identified were recruited and consented for genomic and DNA stu- apparently causative compound heterozygous SH3TC2 dies under a research protocol approved by the Institutional variants: nonsense p.R954X (g. chr5: 148,406,435 G>A) Review Board of Baylor College of Medicine. All patients and missense p.Y169H alleles (g. chr5: 148,422,281 gave informed consent for participation in this study. A>G) [2]. The two alleles satisfied multiple criteria for disease causation: both were validated with alternate DNA preparation methods technologies; the nonsense p.R954X allele had been pre- Blood was directly collected in PAXgene Blood DNA tubes viously reported in unrelated CMT families and corro- and DNA was isolated using the PAXgene Blood DNA kit borated with functional studies; each segregated (PreAnalytiX, Qiagen, Valencia, CA, USA). The quality of faithfully in the pedigree and no other lesion was dis- the DNA sample was ascertained by electrophoresis and covered in the locus despite adequate coverage of all determined to be of high quality (size >23 kb) with no visi- coding bases with NGS reads. Further, each allele faith- ble degradation. Quantity was determined using standard fully independently segregated with additional different Pico Green assays. mild phenotypes observed in other family members - susceptibility to carpal tunnel syndrome (presumably Description of NimbleGen VCRome 2.1 exome capture due to loss-of-function nonsense mutation) and an elec- design trophysiologically identified subclinical axonopathy (mis- In the current methods, the HGSC-design ‘VCRome 2.1’ sense allele). reagent [7] was used for exome capture. This NimbleGen Unresolved issues in the study included discovery of probe set targets the Vega [8], CCDS, and RefSeq gene additional reportedly pathogenic alleles at other loci, models, including predicted genes within RefSeq, as well related to potentially medically actionable conditions (inci- as microRNA (miRNA) [9] and regulatory regions for a dental or secondary findings). For example, the proband total target size of 42 Mb. Thus, exome capture sequen- was suggested to have a dominant variant that was causa- cing will identify SNPs and indels in protein coding tive for adrenoleukodystrophy (ALD, MIM #300100) [3]; regions, exon flanking sequences (including intron splice ABCD1, chrX:153,008,483 G>A; p.G608D, as well as to be sites), regulatory regions, and small non-coding RNAs (for homozygous for an allele causative for spinal muscular example, microRNAs). atrophy with respiratory distress type 1 (SMARD, MIM #604320) [4]; IGHMBP2, chr11:68,705,674C>A; pT879K. Illumina exome sequencing on GAII and HiSeq These variants were confirmed by Sanger sequencing and Library construction restriction endonuclease digestion (Figure 1). The proband Genomic DNA samples were constructed into Illumina was also found by WGS to be homozygous for reported PairEnd pre-capture libraries according to the manufac- causative mutations in three other Mendelian disease turer’s protocol (Illumina Multiplexing_SamplePrep_- genes. The possibility for erroneous entries in public Guide_1005361_D) with modifications as described in the Lupski et al. Genome Medicine 2013, 5:57 Page 3 of 17 http://genomemedicine.com/content/5/6/57 Figure 1 Confirmation and segregation by endonuclease restriction digestion of mutations presumed to represent incidental findings. The upper gel shows restriction digestion using the HphI restriction enzyme for the p.G608D mutation in ABCD1, causative for adrenoleukodystrophy (ALD). All tested individuals, none of which presented with ALD, are shown to be heterozygous for the mutation, including all males whom are hemizygous for genes on the × chromosome. The lower gel shows restriction digestion using the BtgI restriction enzyme for the p.T879K mutation in IGHMBP2, putatively causative for spinal muscular atrophy with respiratory distress type 1 (SMARD1). Random segregation and zygosity for this variant can be observed in this family; none of the individual subjects present with SMARD. BCM-HGSC Illumina Barcoded Paired-End Capture adaptor sequences. Post-capture LM-PCR amplification Library Preparation protocol. The complete library and was performed using the 2X SOLiD Library
Load more

Recommended publications
  • Inherited Neuropathies
    407 Inherited Neuropathies Vera Fridman, MD1 M. M. Reilly, MD, FRCP, FRCPI2 1 Department of Neurology, Neuromuscular Diagnostic Center, Address for correspondence Vera Fridman, MD, Neuromuscular Massachusetts General Hospital, Boston, Massachusetts Diagnostic Center, Massachusetts General Hospital, Boston, 2 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology Massachusetts, 165 Cambridge St. Boston, MA 02114 and The National Hospital for Neurology and Neurosurgery, Queen (e-mail: [email protected]). Square, London, United Kingdom Semin Neurol 2015;35:407–423. Abstract Hereditary neuropathies (HNs) are among the most common inherited neurologic Keywords disorders and are diverse both clinically and genetically. Recent genetic advances have ► hereditary contributed to a rapid expansion of identifiable causes of HN and have broadened the neuropathy phenotypic spectrum associated with many of the causative mutations. The underlying ► Charcot-Marie-Tooth molecular pathways of disease have also been better delineated, leading to the promise disease for potential treatments. This chapter reviews the clinical and biological aspects of the ► hereditary sensory common causes of HN and addresses the challenges of approaching the diagnostic and motor workup of these conditions in a rapidly evolving genetic landscape. neuropathy ► hereditary sensory and autonomic neuropathy Hereditary neuropathies (HN) are among the most common Select forms of HN also involve cranial nerves and respiratory inherited neurologic diseases, with a prevalence of 1 in 2,500 function. Nevertheless, in the majority of patients with HN individuals.1,2 They encompass a clinically heterogeneous set there is no shortening of life expectancy. of disorders and vary greatly in severity, spanning a spectrum Historically, hereditary neuropathies have been classified from mildly symptomatic forms to those resulting in severe based on the primary site of nerve pathology (myelin vs.
    [Show full text]
  • Lupo Et Al. Vincenzo Lupo , Máximo I
    Lupo et al. MUTATIONS IN THE SH3TC2 PROTEIN CAUSING CHARCOT-MARIE-TOOTH DISEASE TYPE 4C AFFECT ITS LOCALIZATION IN THE PLASMA MEMBRANE AND ENDOCYTIC PATHWAY Vincenzo Lupo1,2, Máximo I. Galindo1,2, Dolores Martínez-Rubio1,2, Teresa Sevilla3,4, Juan J. Vílchez3,4, Francesc Palau1,2, Carmen Espinós2. 1. Genetics and Molecular Medicine Unit, Instituto de Biomedicina de Valencia (IBV), CSIC, 46010 Valencia, Spain. 2. CIBER de Enfermedades Raras (CIBERER), 46010 Valencia, Spain. 3. Neurology Service, Hospital Universitari La Fe, 46009 Valencia, Spain. 4. CIBER de Enfermedades Neurodegenerativas (CIBERNED), 46009 Valencia, Spain. Corresponding author: Dr, Francesc Palau Genetics and Molecular Medicine Unit Instituto de Biomedicina de Valencia (IBV), CSIC c/ Jaume Roig, 11. 46010 Valencia, Spain Fax: + 34 96 369 0800 Telephone number: + 34 96 339 3773 Email: [email protected] 1 Lupo et al. Abstract (250 words) Mutations in SH3TC2 cause Charcot-Marie-Tooth disease (CMT) type 4C, a demyelinating inherited neuropathy characterized by early onset and scoliosis. Here we demonstrate that SH3TC2 is expressed in several components of the endocytic pathway including early endosomes, late endosomes and clathrin-coated vesicles close to the trans-Golgi network, and in the plasma membrane. Myristoylation of SH3TC2 in glycine 2 is necessary but not sufficient for the proper location of the protein in the cell membranes. In addition to myristoylation, correct anchoring also needs the presence of SH3 and TPR domains. Mutations that cause a stop codon and produce premature truncations that remove most of the TPR domains are expressed as the wild type protein. In contrast, missense mutations in or around the region of the first TPR domain are not expressed in early endosomes, have reduced expression in plasma membrane and late endosomes, and are variably expressed in clathrin-coated vesicles.
    [Show full text]
  • Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C
    International Journal of Molecular Sciences Article Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C Silvia Cipriani 1,2,3,†, Vietxuan Phan 4,†, Jean-Jacques Médard 5,6, Rita Horvath 7, Hanns Lochmüller 8,9,10,11 , Roman Chrast 5,6, Andreas Roos 4,12,† and Sally Spendiff 1,10,*,† 1 John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; [email protected] 2 INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy 3 Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy 4 Leibniz-Institut für Analytische Wissenschaften -ISAS- e.V.; Otto-Hahn-Strasse 6b, 44227 Dortmund, Germany; [email protected] (V.P.); [email protected] (A.R.) 5 Department of Neuroscience, Karolinska Institutet, 171 65 Stockholm, Sweden; [email protected] (J.-J.M.); [email protected] (R.C.) 6 Department of Clinical Neuroscience, Karolinska Institutet, 171 65 Stockholm, Sweden 7 Department of Clinical Neurosciences, University of Cambridge, John Van Geest Cambridge Centre for Brain Repair, Forvie, Robinson way, Cambridge Biomedical Campus, Cambridge CB2 0PY, UK; [email protected] 8 Department of Neuropediatrics and Muscle Disorders, Medical Center-University of Freiburg, Mathildenstrasse 1, 79106 Freiburg, Germany; [email protected] 9 Centro Nacional de Análisis Genómico, Center for Genomic Regulation, Barcelona Institute of Science and Technology, Baldri I reixac 4, 08028 Barcelona, Spain 10 Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada 11 Division of Neurology, Department of Medicine, The Ottawa Hospital, Riverside Drive, Ottawa, ON K1H 7X5, Canada 12 Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, Centre for Neuromuscular Disorders in Children, University Children’s Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany * Correspondence: [email protected]; Tel.: +1-613-737-7600 (ext.
    [Show full text]
  • Impacts of Massively Parallel Sequencing for Genetic Diagnosis of Neuromuscular Disorders
    Acta Neuropathol (2013) 125:173–185 DOI 10.1007/s00401-012-1072-7 REVIEW Impacts of massively parallel sequencing for genetic diagnosis of neuromuscular disorders Nasim Vasli • Jocelyn Laporte Received: 8 October 2012 / Revised: 27 November 2012 / Accepted: 28 November 2012 / Published online: 7 December 2012 Ó Springer-Verlag Berlin Heidelberg 2012 Abstract Neuromuscular disorders (NMD) such as neu- We remind the challenges and benefit of obtaining an ropathy or myopathy are rare and often severe inherited accurate genetic diagnosis, introduce the massively parallel disorders, affecting muscle and/or nerves with neonatal, sequencing technology and its novel applications in diag- childhood or adulthood onset, with considerable burden for nosis of patients, prenatal diagnosis and carrier detection, the patients, their families and public health systems. and discuss the limitations and necessary improvements. Genetic and clinical heterogeneity, unspecific clinical fea- Massively parallel sequencing synergizes with clinical and tures, unidentified genes and the implication of large and/or pathological investigations into an integrated diagnosis several genes requiring complementary methods are the approach. Clinicians and pathologists are crucial in patient main drawbacks in routine molecular diagnosis, leading to selection and interpretation of data, and persons trained in increased turnaround time and delay in the molecular data management and analysis need to be integrated to the validation of the diagnosis. The application of massively diagnosis pipeline. Massively parallel sequencing for parallel sequencing, also called next generation sequenc- mutation identification is expected to greatly improve ing, as a routine diagnostic strategy could lead to a rapid diagnosis, genetic counseling and patient management. screening and fast identification of mutations in rare genetic disorders like NMD.
    [Show full text]
  • Genomic Diagnostics Within a Medically Underserved Population: Efficacy and Implications
    © American College of Medical Genetics and Genomics ORIGINAL RESEARCH ARTICLE Genomic diagnostics within a medically underserved population: efficacy and implications Kevin A. Strauss, MD1, Claudia Gonzaga-Jauregui, PhD2, Karlla W. Brigatti, MS1, Katie B. Williams, MD, PhD1, Alejandra K. King, PhD2, Cristopher Van Hout, PhD2, Donna L. Robinson, CRNP1, Millie Young, RNC1, Kavita Praveen, PhD2, Adam D. Heaps, MS1, Mindy Kuebler, MS1, Aris Baras, MD2, Jeffrey G. Reid, PhD2, John D. Overton, PhD2, Frederick E. Dewey, MD2, Robert N. Jinks, PhD3, Ian Finnegan, BA3, Scott J. Mellis, MD, PhD2, Alan R. Shuldiner, MD2 and Erik G. Puffenberger, PhD1 Purpose: We integrated whole-exome sequencing (WES) and Compared to trio analysis, “family” WES (average seven exomes chromosomal microarray analysis (CMA) into a clinical workflow per proband) reduced filtered candidate variants from 22 ± 6to to serve an endogamous, uninsured, agrarian community. 5 ± 3 per proband. Nineteen (51%) alleles were de novo and 17 Methods: Seventy-nine probands (newborn to 49.8 years) who (46%) inherited; the latter added to a population-based diagnostic presented between 1998 and 2015 remained undiagnosed after panel. We found actionable secondary variants in 21 (4.2%) of 502 biochemical and molecular investigations. We generated WES data subjects, all of whom opted to be informed. for probands and family members and vetted variants through Conclusion: CMA and family-based WES streamline and rephenotyping, segregation analyses, and population studies. economize diagnosis of rare genetic disorders, accelerate novel Results: The most common presentation was neurological disease gene discovery, and create new opportunities for community-based (64%). Seven (9%) probands were diagnosed by CMA.
    [Show full text]
  • Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy
    The new england journal of medicine original article Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy James R. Lupski, M.D., Ph.D., Jeffrey G. Reid, Ph.D., Claudia Gonzaga-Jauregui, B.S., David Rio Deiros, B.S., David C.Y. Chen, M.Sc., Lynne Nazareth, Ph.D., Matthew Bainbridge, M.Sc., Huyen Dinh, B.S., Chyn Jing, M.Sc., David A. Wheeler, Ph.D., Amy L. McGuire, J.D., Ph.D., Feng Zhang, Ph.D., Pawel Stankiewicz, M.D., Ph.D., John J. Halperin, M.D., Chengyong Yang, Ph.D., Curtis Gehman, Ph.D., Danwei Guo, M.Sc., Rola K. Irikat, B.S., Warren Tom, B.S., Nick J. Fantin, B.S., Donna M. Muzny, M.Sc., and Richard A. Gibbs, Ph.D. ABSTRACT BACKGROUND Whole-genome sequencing may revolutionize medical diagnostics through rapid From the Department of Molecular and identification of alleles that cause disease. However, even in cases with simple pat- Human Genetics (J.R.L., J.G.R., C.G.-J., M.B., F.Z., P.S., D.M.M., R.A.G.), the Hu- terns of inheritance and unambiguous diagnoses, the relationship between disease man Genome Sequencing Center (J.G.R., phenotypes and their corresponding genetic changes can be complicated. Compre- D.R.D., D.C.Y.C., L.N., M.B., H.D., C.J., hensive diagnostic assays must therefore identify all possible DNA changes in each D.A.W., D.M.M., R.A.G.), the Center for Medical Ethics and Health Policy (A.L.M.), haplotype and determine which are responsible for the underlying disorder.
    [Show full text]
  • Demyelinating Prenatal and Infantile Developmental Neuropathies
    Journal of the Peripheral Nervous System 17:32–52 (2012) REVIEW Demyelinating prenatal and infantile developmental neuropathies Eppie M. Yiu1,2 and Monique M. Ryan1,2,3 1Children’s Neuroscience Centre, Royal Children’s Hospital; 2Murdoch Childrens Research Institute, Flemington Rd, Parkville, 3052, Victoria, Australia; and 3Department of Paediatrics, The University of Melbourne, Australia Abstract The prenatal and infantile neuropathies are an uncommon and complex group of conditions, most of which are genetic. Despite advances in diagnostic techniques, approximately half of children presenting in infancy remain without a specific diagnosis. This review focuses on inherited demyelinating neuropathies presenting in the first year of life. We clarify the nomenclature used in these disorders, review the clinical features of demyelinating forms of Charcot-Marie-Tooth disease with early onset, and discuss the demyelinating infantile neuropathies associated with central nervous system involvement. Useful clinical, neurophysiologic, and neuropathologic features in the diagnostic work-up of these conditions are also presented. Key words: Charcot-Marie-Tooth disease, Dej´ erine–Sottas´ disease, demyelination, paediatric, peripheral neuropathy Introduction Aetiology The prenatal and infantile neuropathies are an In a large cohort of 260 children with biopsy- uncommon and complex group of conditions with confirmed peripheral neuropathy, 50 (19.2%) were broad phenotypic and genotypic diversity. Most symptomatic in infancy, of whom 48% had a infantile neuropathies have a genetic basis. This review demyelinating and 42% an axonal disorder (Wilmshurst focuses on inherited demyelinating neuropathies et al., 2003). Whilst many of these cases presented presenting in the first year of life. Axonal neuropathies prior to the era of genetic diagnosis, 20 children presenting during this period will be reviewed fell under the rubric of Charcot-Marie-Tooth disease separately.
    [Show full text]
  • Pathogenic Alleles, Clan Genomics and the Complex Architecture of Human Disease
    Pathogenic alleles, clan genomics and the complex architecture of human disease “High-throughput Sequencing – Applications and Analyses Oslo University 200th, NORWAY October 28, 2011 James R. Lupski, M.D., Ph.D., D.Sc. Department of Molecular & Human Genetics & Department of Pediatrics Baylor College of Medicine & Texas Children’s Hospital Houston, TX http://www.bcm.edu/geneticlabs/ Disclosure J.R.L. is a consultant for: NO affiliation with: Athena Diagnostics Life Technologies, Inc NOR 23andMe Applied BioSysytems, Inc Ion Torrent Systems Inc. Co-Inventor on Diagnostic Patents: UNITED STATES: 5,294,533 (issued 03/15/94); 5,306,616 (issued 04/26/94); 5,523,217 (issued 06/04/96); 5,599,920 (issued 02/04/97); 5,667,968 (issued 09/16/97);5,780,223 (issued 07/14/98); 6,132,954 (issued 10/19/00); 6,713,300 (issued 03/30/04); 7,141,420 (issued 11/28/06); 7,189,511 (issued 03/13/07); 7,192,579 (issued 03/20/07); 7,273,698 (issued 09/25/07). EUROPEAN: 0424473 (issued 05/08/96), 0610396 (issued 01/17/01), 0989805 (issued 01/11/06). The Medical Genetics Laboratories (MGL) of the Dept of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular diagnostic testing. MGL, http://www.bcm.edu/geneticlabs/ A story about Charcot-Marie-Tooth disease CMT: clinical & genetic aspects The CMT1A duplication - a paradigm for CNV mutation & mechanisms for CNV formation CMT mutational load - gene load? locus load? or genomic load? - SNP + CNV Personal genome sequencing: CMT Genetic contributions to inherited and apparently acquired neurologic dz CMT: clinical & genetic aspects The CMT1A duplication - a paradigm for CNV mutation & mechanisms for CNV formation CMT mutational load - gene load? locus load? or genomic load? - SNP + CNV Personal genome sequencing: CMT 1886 in Paris & Cambridge,UK Hereditary Neuropathies CMT research – the first century (105 years!).
    [Show full text]
  • Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy
    The new england journal of medicine original article Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy James R. Lupski, M.D., Ph.D., Jeffrey G. Reid, Ph.D., Claudia Gonzaga-Jauregui, B.S., David Rio Deiros, B.S., David C.Y. Chen, M.Sc., Lynne Nazareth, Ph.D., Matthew Bainbridge, M.Sc., Huyen Dinh, B.S., Chyn Jing, M.Sc., David A. Wheeler, Ph.D., Amy L. McGuire, J.D., Ph.D., Feng Zhang, Ph.D., Pawel Stankiewicz, M.D., Ph.D., John J. Halperin, M.D., Chengyong Yang, Ph.D., Curtis Gehman, Ph.D., Danwei Guo, M.Sc., Rola K. Irikat, B.S., Warren Tom, B.S., Nick J. Fantin, B.S., Donna M. Muzny, M.Sc., and Richard A. Gibbs, Ph.D. ABSTRACT BACKGROUND Whole-genome sequencing may revolutionize medical diagnostics through rapid From the Department of Molecular and identification of alleles that cause disease. However, even in cases with simple pat- Human Genetics (J.R.L., J.G.R., C.G.-J., M.B., F.Z., P.S., D.M.M., R.A.G.), the Hu- terns of inheritance and unambiguous diagnoses, the relationship between disease man Genome Sequencing Center (J.G.R., phenotypes and their corresponding genetic changes can be complicated. Compre- D.R.D., D.C.Y.C., L.N., M.B., H.D., C.J., hensive diagnostic assays must therefore identify all possible DNA changes in each D.A.W., D.M.M., R.A.G.), the Center for Medical Ethics and Health Policy (A.L.M.), haplotype and determine which are responsible for the underlying disorder.
    [Show full text]
  • Genetic Testing for Diagnosis of Inherited Peripheral Neuropathies
    Corporate Medical Policy Genetic Testing for Diagnosis of Inherited Peripheral Neuropathies AHS – M2072 File Name: genetic_testing_for_diagnosis_of_inherited_peripheral_neuropathies Origination: 01/01/2019 Last CAP Review: 07/2021 Next CAP Review: 07/2022 Last Review: 07/2021 Description of Procedure or Service The inherited peripheral neuropathies are a heterogeneous group of diseases that may be inherited in an autosomal dominant, autosomal recessive, or X-linked dominant manner. The inherited peripheral neuropathies can be divided into hereditary motor and sensory neuropathies (such as Charcot-Marie- Tooth disease), hereditary neuropathy with liability to pressure palsies, hereditary sensory and autonomic neuropathies, and other miscellaneous types (e.g., hereditary brachial plexopathy, giant axonal neuropathy). In addition to clinical presentation, nerve conduction studies, and family history, genetic testing can be used to diagnose specific inherited peripheral neuropathies (Kang, 2020a). Related Policies Nerve Fiber Density Testing AHS – M2112 General Genetic Testing, Germline Disorders AHS – M2145 General Genetic Testing, Somatic Disorders AHS – M2146 Celiac Disease Testing AHS – G2043 ***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician. Policy BCBSNC will provide coverage for genetic testing for diagnosis of inherited peripheral neuropathies when it is determined the medical criteria or reimbursement guidelines below are met. Benefits Application This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.
    [Show full text]
  • SH3TC2, a Protein Mutant in Charcot–Marie–Tooth Neuropathy, Links Peripheral Nerve Myelination to Endosomal Recycling
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Serveur académique lausannois doi:10.1093/brain/awq168 Brain 2010: 133; 2462–2474 | 2462 BRAIN A JOURNAL OF NEUROLOGY SH3TC2, a protein mutant in Charcot–Marie–Tooth neuropathy, links peripheral nerve myelination to endosomal recycling Claudia Stendel,1,* Andreas Roos,2,* Henning Kleine,3,# Estelle Arnaud,4,# Murat O¨ zc¸elik,1,# Pa´ris N. M. Sidiropoulos,1,# Jennifer Zenker,4 Fanny Schu¨ pfer,4 Ute Lehmann,3 Radoslaw M. Sobota,5 David W. Litchfield,6 Bernhard Lu¨ scher,3 Roman Chrast,4 Ueli Suter1 and Jan Senderek1 1 Institute of Cell Biology, Department of Biology, ETH Zu¨ rich, Zu¨ rich, Switzerland 2 Institute of Human Genetics, RWTH Aachen University, Aachen, Germany 3 Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany 4 Department of Medical Genetics and Service of Medical Genetics, University of Lausanne and Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland 5 Centre for Experimental Bioinformatics, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark 6 Department of Biochemistry, University of Western Ontario, London, Canada *These authors contributed equally to this work. #These authors contributed equally to this work. Correspondence to: Dr Jan Senderek, Institute of Cell Biology, ETH Zu¨ rich, Schafmattstr 18, 8093 Zu¨ rich, Switzerland E-mail: [email protected] Patients with Charcot–Marie–Tooth neuropathy and gene targeting in mice revealed an essential role for the SH3TC2 gene in peripheral nerve myelination. SH3TC2 expression is restricted to Schwann cells in the peripheral nervous system, and the gene product, SH3TC2, localizes to the perinuclear recycling compartment.
    [Show full text]
  • A Yeast-Based Model for Hereditary Motor and Sensory Neuropathies: a Simple System for Complex, Heterogeneous Diseases
    International Journal of Molecular Sciences Review A Yeast-Based Model for Hereditary Motor and Sensory Neuropathies: A Simple System for Complex, Heterogeneous Diseases Weronika Rzepnikowska 1, Joanna Kaminska 2 , Dagmara Kabzi ´nska 1 , Katarzyna Bini˛eda 1 and Andrzej Kocha ´nski 1,* 1 Neuromuscular Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, 02-106 Warsaw, Poland; [email protected] (W.R.); [email protected] (D.K.); [email protected] (K.B.) 2 Institute of Biochemistry and Biophysics Polish Academy of Sciences, 02-106 Warsaw, Poland; [email protected] * Correspondence: [email protected] Received: 19 May 2020; Accepted: 15 June 2020; Published: 16 June 2020 Abstract: Charcot–Marie–Tooth (CMT) disease encompasses a group of rare disorders that are characterized by similar clinical manifestations and a high genetic heterogeneity. Such excessive diversity presents many problems. Firstly, it makes a proper genetic diagnosis much more difficult and, even when using the most advanced tools, does not guarantee that the cause of the disease will be revealed. Secondly, the molecular mechanisms underlying the observed symptoms are extremely diverse and are probably different for most of the disease subtypes. Finally, there is no possibility of finding one efficient cure for all, or even the majority of CMT diseases. Every subtype of CMT needs an individual approach backed up by its own research field. Thus, it is little surprise that our knowledge of CMT disease as a whole is selective and therapeutic approaches are limited. There is an urgent need to develop new CMT models to fill the gaps.
    [Show full text]